Yl piperidol(4)ester 3-beta-acetoxy 11-oxo noroleanene-(12) 20 beta-carboxylic acid n-meth

ABSTRACT

3-B-ACETOXY 11-OXO NOROLEANENE-(12) 20B-CARBOXYLIC ACID N-METHYL PIPERIDOL-(4) ESTER AND PHYSIOLOGICALLY TOLERABLE ACID ADDITION SALTS THEREOF THAT ARE ORALLY ADMINISTERABLE AND HAVE SUPERIOR INFLAMMATION INHIBITING EFFECTS ARE PREPARED BY REACTING 3B-ACETOXY 11-OXO NOROLEANENE-(12) 20B-CARBOXYLIC ACID OR A FUNCTIONAL DERIVATIVE THEREOF WITH N-METHYL PIPERIDOL-(4).

United States Patent M 3,758,484 3-p-ACETOXY 11-0X0 NOROLEANENE-(12) 20,8- CARBOXYLIC ACID N-METHYL PIPERIDOL- (4) ESTER Helmut Kraft, Neckarhausen, Frank Zimmermann, Mannheim, and Hans-Peter Hofmann, Ludwigshafen, Germany, assignors to Knoll AG, Chemische Fabriken, Ludwigshafen (Rhine), Germany No Drawing. Filed Aug. 25, 1971, Ser. No. 174,924 Claims priority, application Germany, Sept. 2, 1970, P 20 43 479.1 Int. Cl. C07d 29/24 US. Cl. 260-29356 3 Claims ABSTRACT OF THE DISCLOSURE 3-j8-acetoxy ll-oxo noroleanene-(12) ZOfl-carboxylic acid N-methyl piperidol-(4) ester and physiologically tolerable acid addition salts thereof that are orally ad- 'ministerable and have superior inflammation inhibiting eflects are prepared by reacting 3,8-acetoxy ll-oxo noroleanenc-(lZ) 20l3-carboxylic acid or a functional derivative thereof with N-methyl piperidol-(4).

The present invention relates to a derivative of glycyrrhetinic acid, a process for the preparation thereof and a pharmaceutical composition containing such a derivative.

It is known from the work of R. S. H. Finney and G. F. Somers [1. Pharm. Pharmacol. 10, 613 (1958)] that glycyrrhetinic acid (3 3 hydroxy 11 oxo-noroleanene- (12)-20fl-carboxylic acid) has inflammation inhibiting properties. The introduction of an acetyl group into the 3-position of glycyrrhetinic acid does not change the strength of the inflammation inhibiting effect.

It has now been discovered that a certain ester of 3 8- acetoxy glycyrrhetinic acid has superior inflammation-inhibiting properties.

The present invention therefore is concerned with 3,3- acetoxy 11 oxo-noroleanene-( 12)-20fi-carboxylic-acid- N-methyl-piperidol-(4)-ester of the formula CHaCO-O i HsC CH3 Patented Sept. 11, 1973 The following are among acids considered to be physiologically compatible: hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, tartaric acid, fumaric acid, citric acid and sulfamic acid.

The Kaolin-oedema test on rat paws (I. Hillebrecht, Arzneimittelforschung 4, 607 (1954)) indicates that the new compound of this invention and the salts thereof have inflammation-inhibiting properties approximately three times greater than Carbenoxolon (sodium salt). Carbenoxolon is 3,8 (3-carboxypropionyloxy)-1l-oxo- 18fi-olean-12-en-30-acid.

In addition, the new compound and its salts lead to a reduction of the ulcer count (0. Munchow, Arzneimittelforschung 4, 341 (1954)) and of the acid secretion in rats whose Pylorus was ligated. (H. Shay, S. A. Koma roy, S. S. Fels, D. Meranze, M. Gruenstein and H. Siplet, Gastroenterology 5, 43 (1945)). With regard to the ulcer protective effect, the new compound and its salts are approximately ten times stronger than Carbenoxolon (sodium salt). In the Lung-oedema test (according to D. Henschler, W. Ross, Naunyn. Schmiedebergs Arch. exp. Bath. Pharmakol. 241, 159 (1961)) the new substances show themselves to be approximately twice as strong as the Carbenoxolon (sodium salt).

Furthermore, the new substances are eight to ten times more compatible than the sodium salt of Carbenoxolon, as shown by the determination of the acute toxicity in the Albino mouse (NMRI) after a single oral dose according to D. J. Finney (Probit Analysis 1962).

The new compound and the salts thereof are therefore well suited for the treatment of disturbances of the alimentary canal, for example, such as gastric or duodenal ulcers. The new active substances are effective when taken orally in doses of approximately l-10 mg./kg. per day.

EXAMPLE 1 A mixture of 3/3-acetoxy-11-oxo-noroleanene-(12)- ZOB-carboxylic acid chloride (8 g., 0.015 mol), N-methylpiperidol-(4) (3.62 g., 0.032 mol) and toluene (180 ml.) is boiled under reflux for 12 hours. After cooling, N-methylpiperidol-(4)-hydrochloride which has separated out, is filtered 05 and diethyl ether (180 ml.) is added to the filtrate. By passing "HCI gas therethrough, the hydrochloride of BB-acetoxy 11 oxo-noroleanene-(12)-20pcarboxylic-acid-N-methyl-piperidol-(4)-ester is precipitated. A yield of 9.1 g., representing 94% of the theoretical yield is obtained. The compound has an empirical formula of C H No HCl and a molecular weight of 646.33.

The product is recrystallized from isopropanol and yields colorless crystals having a melting point of 298- 300" C., and an [(11 of +118.1 (dimethylformamide, c1=0.5).

EXAMPLE 2 A mixture of 3,8-acetoxy-11-oxo noroleanene-( 12) 2018- carboxylic acid chloride (8 g., 0.015 mol), N-methyl piperidol-(4) (3.62 g., 0.032 mol) and toluene 180 ml.) is boiled under reflux for 12 hours. After cooling, N- methyl piperidol-(4) hydrochloride, which has separated out, is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized twice from a mixture of cyclohexane and n-hexane in a ratio of 1:5. 3 B-acetoxy 11-oxo noroleanene-(2) ZOB-carboxylic acid N-methyl piperidol-(4) ester is obtained in a yield representing 95% of the theoretical yield. The compound has an empirical 3 formula of C H 'NO a molecular weight of 609.9, a melting point of 220-221 C. and an [a] of +127.1 (dimethylformamide, c.=0.5

By reacting with the corresponding free acids, the following salts may be obtained:

Sulfate C H NO -H SO molecular weight 707.94, having a melting point of 268 to 269 C. when recrystallized from isopropanol [M =+l07.6 (dimethylformamide, c=0.5)

Sulfamate Q H NO -NH 'HSO molecular weight 706.95 having a melting point of 275 to 276 C. when recrystallized from dimethylformamide [M =+106.2 (dimethylformamide c.*=0.5)

Citrate C H NO -C H O molecular weight 801.98, having a melting point of 216 to 217 C. when crystallized from isopropano-l [ch =+96.4 (dimethylformamide c. =0.5)

EXAMPLE 3 Tablets of the following composition are formed by pressing on a tablet press:

4 {EXAMPLE 4 Sugar coated pills of the following compositions are prepared in the usual manner:

BB-acetoxy ll-oxo noroleanene-(l2) 20fl-carboxylic acid -N-methyl piperidol- (4) ester 35.00 Core material 85.00 Sweetening 80.00

The core material consists of nine parts maize starch, three parts lactose and one part Luviscol VA 64 (registered trademark) (vinylpyrrolidonevinyl acetate mixed polymerisate in a :40 ratio, Pharm. Ind. 1962, 586). The sweetening consists of five parts cane sugar, two parts maize starch, two parts calcium carbonate and one part talc. The resultant sugar coated pills are then provided with a gastric juice-resistant coating.

We claim:

1. 3B-acetoxy 11-oxo noroleanene-(12) 20,9-carboxylic acid N-methyl piperidol-(4) ester.

2. A salt of the compound defined in claim 1 with a physiologically compatible acid.

3. An acid addition salt as defined in claim 2, wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, phosphoric acid, lactic acid, tartaric acid, fumaric acid, citric acid and sulfamic acid. 

